Type IA isolated growth hormone deficiency (IGHD) consistent with compound heterozygous deletions of 6.7 and 7.6 Kb at the GH1 gene locus

Abstract

Isolated growth hormone deficiency (IGHD) may result from deletions/mutations in either GH1 or GHRHR genes. The objective of this study was to characterize the molecular defect in a girl presenting IGHD. The patient was born at 41 weeks of gestation from non-consanguineous parents. Clinical and biochemical evaluation included anthropometric measurements, evaluation of pituitary function, IGF-I and IGFBP-3 levels. Molecular characterization was performed by PCR amplification of GH1 gene and SmaI digestion of two homologous fragments flanking the gene, using genomic DNA from the patient and her parents as templates. At 1.8 years of age the patient presented severe growth retardation (height 61.2 cm, -7.4 SDS), truncal obesity, frontal bossing, doll face, and acromicria. MRI showed pituitary hypoplasia. Laboratory findings confirmed IGHD. GH1 gene could not be amplified in samples from the patient while her parents yielded one fragment of the expected size. SmaI digestion was consistent with the patient being compound heterozygous for 6.7 and 7.6 Kb deletions, while her parents appear to be heterozygous carriers for either the 6.7 or the 7.6 Kb deletions. We have characterized type IA IGHD caused by two different GH1 gene deletions, suggesting that this condition should be considered in severe IGHD, even in non-consanguineous families. Arq Bras Endocrinol Metab. 2012;56(8):558-63

Same Phenotype in Children with Growth Hormone Deficiency and Resistance

“…These children may show facial dysmorphisms such as craniofacial disproportion with hypoplasia of the midface, frontal bossing, doll face, and sparse and fine hair. Their phenotype also includes truncal obesity, acromicria, high-pitched voice, delayed skeletal maturation and dentition, and genital abnormalities like micropenis and delayed puberty [ 8 , 13 ]. Similarly, patients with GHI syndrome show reduced birth length and intrauterine growth retardation and severe postnatal growth failure and short stature in adulthood.…”

“…The first case was a South American small for gestational age girl, born in the 41st week of gestation from nonconsanguineous parents, previously described by Keselman et al [ 8 ]. Neonatal auxological data are shown in Table 1 .…”

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…The high circulating cortisol levels together with the small amount of detectable circulating GH may contribute to the lack of neonatal symptomatic hypoglycemia episodes in GHRHR mutations (22), which typically occurs in severe IGHD due to GH1 gene defects causing complete absence of GH protein. Notably, a child with type 1A IGHD without hypoglycemia and with elevated cortisol levels has recently been reported (29). Basal levels of serum TSH are mildly increased in the IGHD subjects (26), often within the upper normal range.…”

“…The dimensions of hands, feet, scapular and pelvic girth are also reduced, reflecting the effect of GH on bone growth (37). Conversely, the reduction of the cephalic perimeter (−2.7 SDS) is less accentuated than stature (26,29) and facial height (−4.3 SDS) (61), causing a disproportion between the calvarium and the face (Fig. 3), resulting in a 'doll' or cherubim angel facies.…”

“…These features have been published in 42 different publications (2,19,22,25,27,29,30,31,32,33,36,37,38,40,41,44,45,46,47,48,49,50,51,52,53,54,56,57,61,62,63,64,66,67,68,74,75,76,77,78,79,80). We have used this experiment of nature to discover 'usual laws of nature' as suggested by William Harvey, and to understand some aspects of more common conditions such as short stature, insulin resistance, diabetes, atherosclerosis, osteoporosis, cancer and ultimately longevity.…”